Is DYNC1H1 p.Arg3446Cys (c.10336C>T) pathogenic?

DYNC1H1 p.Arg3446Cys (c.10336C>T) is classified Uncertain significance in DYNC1H1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). AlphaMissense: likely benign (0.2993); Very rare (popmax 0.00223%, eas); Associated with Charcot-Marie-Tooth disease axonal type 2O.

What condition is associated with DYNC1H1 p.Arg3446Cys (c.10336C>T)?

DYNC1H1 p.Arg3446Cys (c.10336C>T) is associated with Charcot-Marie-Tooth disease axonal type 2O (ClinVar).

How common is DYNC1H1 p.Arg3446Cys (c.10336C>T) in the general population?

DYNC1H1 p.Arg3446Cys (c.10336C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DYNC1H1 p.Arg3446Cys (c.10336C>T)?

AlphaMissense predicts likely benign (score 0.2993) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Arg3446Cys

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2O inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.10336C>T · rs1407151844 · VCV656221

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2993 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Charcot-Marie-Tooth disease axonal type 2O

Computational evidence

Protein change
AlphaMissense	0.2993	likely benign
REVEL	0.729	pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.38	unconstrained · MANE · 7,350 bp · p 6.9e-63 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,894 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00149% 24/1,614,062 alleles · very rare exomes 23/1,461,888 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,894
European (non-Finnish)	0.00186%	53,639
Finnishnot grpmax-eligible	0.00156%	64,020

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DYNC1H1
Protein: p.Arg3446Cys
Coding: c.10336C>T
MANE Select: NM_001376
dbSNP: rs1407151844
Type: single nucleotide variant
Location: chr14:102033407 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 3446: the 'stalk' region

Full DYNC1H1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease axonal type 2O — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant Charcot-Marie-Tooth disease type 2O (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

DYNC1H1 p.Arg1567Gln Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg1623Gln Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg1962Cys Pathogenic ★★ same condition
DYNC1H1 p.Arg1962His Likely pathogenic ★★ same condition
DYNC1H1 p.Arg2332Cys Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg251Ser Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg264Leu Pathogenic ★★ same condition
DYNC1H1 p.Arg292Trp Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dync1h1-p-arg3446cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown